tbuckley/cabot-search huggingface dataset:
Diversity, equity, and inclusion (DEI) champions: Lessons learned and implications for future programming to support cancer clinical trials.
Authors: Colmar Figueroa-Moseley, Lucy Gansauer, Jessica Dreger McDermott, Manuel Ricardo Espinoza Gutarra, Gayathri Nagaraj, Patricia A. Robinson, Rick Bangs, Allison Caban-Holt
Journal: Journal of Clinical Oncology (2023)

e18529 Background: Improving diversity and representativeness in SWOG Cancer Research Network (SWOG) clinical trials is critical for addressing disparities in prevention, detection, treatment, supportive care, and mortality among patients with cancer diagnosis. Understanding the needs of underrepresented groups (URGs) and building relationships and trust between these populations and researchers can help overcome barriers to study recruitment. SWOG developed a formal organization structure to provide evidence-based guidance for increasing diverse representation in SWOG research. Methods: Funded through a grant from Genentech and the Hope Foundation, SWOG developed a methodology and field guide to improve representativeness in clinical trials. This methodology includes analyzing the current clinical trial portfolio, reviewing study sites and inclusion/exclusion criteria, refining protocol and accrual plans to be more inclusive, implementing changes, and sharing findings with study teams and communities. Five DEI Champions were selected to work with 5 research committees including Gastrointestinal, Lung, Breast, and Genitourinary Cancers and Multiple Myeloma to identify action plans. The Champions provided tools, evidence, and strategies to implement SWOG’s DEI methodology, provided countermeasures for studies not meeting prespecified enrollment benchmarks, and analyzed and reported participation across the SWOG clinical trial portfolio. Champions, study teams, and committees all implemented strategies and structure for research program modifications and policies. Results: Four of the 5 research committees showed significant improvements in infrastructure and implementation of DEI. Factors that improved DEI within SWOG research committees included a willingness of the committee to engage in DEI work; the infrastructure in place to support the implementation of DEI; the tumor sites being studied, and cross-committee collaborations on research protocols (Veterans, Patient Advocacy, Recruitment &amp; Retention, and Palliative &amp; Support Care). Conclusions: The DEI Champion role is an important strategy that engages cancer researchers and staff in DEI improvement activities and improves infrastructure and recruitment of URGs to clinical trials. Further research is needed to determine the impact of DEI champions on cancer clinical trial participation.
Intracranial and systemic efficacy of repotrectinib in advanced <i>ROS1</i> fusion-positive (<i>ROS1</i>+) non-small cell lung cancer (NSCLC) and central nervous system metastases (CNS mets) in the phase 1/2 TRIDENT-1.
Authors: Jessica Jiyeong Lin, Alexander E. Drilon, Byoung Chul Cho, Enriqueta Felip, Adrianus De Langen, Nong Yang, Sang-We Kim, Shun Lu, Steven Chuan-Hao Kao, Vamsidhar Velcheti, Denis Lucien MORO SIBILOT, Benjamin J. Solomon, Rafal Dziadziuszko, Matthew G Krebs, Parneet Kaur Cheema, Christophe Alfons Dooms, Shanna Stopatschinskaja, Denise Trone, Felipe Ades, D. Ross Camidge
Journal: Journal of Clinical Oncology (2023)

9017 Background: Repotrectinib is a next-generation ROS1 and TRK tyrosine kinase inhibitor (TKI) that has demonstrated durable activity with a manageable safety profile in TKI-naïve and TKI-pretreated patients (pts) with advanced ROS1+ NSCLC. We report the first analysis of outcomes on repotrectinib in pts with ROS1+ NSCLC by baseline (BL) CNS met status in the global pivotal phase 1/2 TRIDENT-1 trial (NCT03093116). Methods: Pts with ROS1+ NSCLC were assigned to 4 cohorts by treatment history: ROS1 TKI-naïve, 1 ROS1 TKI and no chemotherapy (chemo), 1 ROS1 TKI and 1 platinum-based chemo, and 2 ROS1 TKIs and no chemo. Treated or untreated asymptomatic CNS mets were permitted. Brain scans were mandated for all pts in phase 2 at screening and at protocol-specified intervals until progression. Endpoints included confirmed objective response rate (cORR) and duration of response (DOR) by blinded independent central review (BICR; RECIST v1.1); intracranial ORR (icORR) in pts with measurable brain mets at BL by BICR per mRECIST v1.1; and safety. Results: In pts with BL measurable CNS mets who were TKI-naïve (n = 8) and in those with 1 TKI and no chemo (n = 12), icORR (95% CI) was 88% (47-100) and 42% (15-72), respectively. At data cutoff (June 20, 2022), 0 of 7 responders in the TKI-naïve cohort and 2 of 5 in the cohort with 1 prior TKI and no chemo had intracranial progression or death; intracranial DOR range was 1.9-14.8+ mo (TKI-naïve) and 3.0-11.1+ mo (1 TKI and no chemo), with 86% and 80% of pts with an intracranial response remaining on treatment, respectively. Median follow-up and systemic response by CNS met status are shown in the Table. In pts with ROS1+ NSCLC with (n = 118) or without (n = 178) CNS mets, most common any-grade neurologic treatment-emergent adverse events were dizziness (57% / 63%), dysgeusia (42% / 53%), paresthesia (32% / 34%), headache (27% / 12%), ataxia (17% / 22%), and memory impairment (14% / 10%). Conclusions: In TRIDENT-1, repotrectinib showed durable clinical activity in ROS1 TKI-naïve and -pretreated pts with or without BL CNS mets, including intracranial responses. Repotrectinib safety profile was similar in pts with ROS1+ NSCLC with or without CNS mets. Clinical trial information: NCT03093116 . [Table: see text]
Cannabis extract for secondary prevention of chemotherapy-induced nausea and vomiting: Results of a phase II/III, placebo-controlled, randomised trial.
Authors: Antony Mersiades, Adrienne Kirby, Martin R. Stockler, Annette Tognela, Ian N. Olver, Rachael L. Morton, Paul Haber, Anna Walsh, Yvonne Lee, Ehtesham A. Abdi, Stephen Della-Fiorentina, Morteza Aghmesheh, Peter Fox, Karen P. Briscoe, Jasotha Sanmugarajah, Gavin M. Marx, Ganessan Kichenadasse, Helen Wheeler, John Simes, Peter S. Grimison
Journal: Journal of Clinical Oncology (2023)

12019 Background: The aim of this multi-centre, randomised, placebo-controlled, phase II/III trial was to determine the efficacy of adding an oral THC/CBD (tetrahydrocannabinol/cannabidiol) cannabis extract in adults who experience CINV during moderate and highly emetogenic intravenous chemotherapy regimens despite guideline-consistent anti-emetic prophylaxis. The phase II crossover component has been published (Grimison et al, AnnOnc 2020). Here we report the definitive results from the combined phase II/III components with a planned sample size of 250 patients. Methods: For the definitive phase III component, participants were randomised 1:1 to receive, oral THC 2.5mg/CBD 2.5mg (Tilray TN-TC11M) capsules TDS days -1 to 5, or placebo (in addition to guideline-consistent anti-emetics including rescue medications) for cycles A, B and C. Primary endpoint was the difference in gaining a ‘complete response’ (no emesis and no use of rescue medications) during 0-120 hours from chemotherapy for cycle A. Results: Complete response was achieved in 24% and 8% with THC/CBD and placebo, respectively (absolute difference 16%, P-value 0.01). The study closed early due to slow accrual without knowledge of study outcomes, with a total of 147 patients recruited 2016-22 (pilot n=78, definitive n=69). Median age was 56 years (range 25 to 80), 78% were females, 39% reported historic cannabis use, 65% were treated with curative intent. Most common regimens were doxorubicin/cyclophosphamide (AC, 31%), and fluorouracil/oxaliplatin (FOLFOX, 17%), 97% received corticosteroid &amp; 5-HT3 antagonist, 80% received NK-1 antagonist, 10% received olanzapine. Efficacy and safety are shown in the table. No SAEs were attributed to THC/CBD. Conclusions: Oral THC/CBD was associated with a significant increase in the proportion of patients achieving a complete response in chemotherapy-induced nausea and vomiting and was well tolerated, representing an effective new treatment in the management of this condition. Future analyses will report quality of life and cost-effectiveness. Funding from NSW Government Dept of Health. Drug supply by Tilray. Clinical trial information: ACTRN12616001036404 . [Table: see text]
The impact of homologous recombination deficiency on first-line adjuvant chemotherapy and first-line PARPi maintenance therapy in Chinese patients with epithelial ovarian cancer.
Authors: Lei Li, Yu Gu, Mengpei Zhang, Xiaohua Shi, Zhe Li, Xinyun Xu, Tianqi Sun, Yu Dong, Chao Xue, Xiaoru Zhu, Ran Lv, Kai Jiao, Xuwo Ji, Zhiyong Liang, Ying Jin, Rutie Yin, Ming Wu, Han Liang
Journal: Journal of Clinical Oncology (2023)

e17573 Background: Homologous recombination deficiency (HRD) testing has been approved by FDA for selecting epithelial ovarian cancer (EOC) patients who may benefit from the first-line poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy. However, the effects of HRD on the clinical outcomes of first-line chemotherapy and first-line PARPi maintenance therapy have not been rigorously evaluated in Chinese EOC patients. Methods: We developed a customized sequencing panel named “Precision Human HRD Assay”.This HRD assay contains two sets of probes, HRD-score probes (~50K) and DDR-gene probes, which were used to evaluate HRD score and genotype 36 DDR genes. Then we applied it to two large Chinese EOC patient cohorts and performed a retrospective analysis of progression-free survival (PFS) and overall survival (OS) estimated using the Kaplan-Meier method. Results: In the first-line adjuvant chemotherapy cohort (FACT, N = 380), HRD status significantly improved PFS (median, 15.6 months vs. 9.4 months; HR, 0.688; 95% CI, 0.526 to 0.899; P = 0.003) and OS (median, 89.5 months vs. 60.9 months; HR, 0.636; 95% CI, 0.423 to 0.955; P = 0.008). In the first-line PARPi maintenance therapy cohort (FPMT, N = 83), HRD status significantly improved PFS (median, NA vs 12 months; HR, 0.438; 95% CI, 0.201 to 0.957; P = 0.033) and OS (median, NA vs NA months; HR, 0.12; 95% CI, 0.029 to 0.505; P = 0.001). Conclusions: Our results demonstrate that HRD status is a significant predictor for PFS and OS in both first-line chemotherapy and first-line PARPi maintenance therapy, providing strong real-world evidence for conducting genetic testing and improving clinical recommendations for Chinese EOC patients.
ALMB-0168, a novel Cx43 hemichannel agonist monoclonal antibody, for metastatic or unresectable osteosarcoma after standard chemotherapy: A multicenter, open-label, single-arm, phase 1 study.
Authors: Jingnan Shen, Wei Guo, Jin Wang, Xianbiao Xie, Lu Xie, Jie Xu, Chen Jing, Jianhua Lin, Xianan Li, Yong Zhou, Guowen Wang, Xiaojing Zhang, Yao Weitao, Yang Dong, Zhaoming Ye, Li Wang, Yanyan Zeng, Yongyong Wu, Xiugao Yang, Yanfeng Zhang
Journal: Journal of Clinical Oncology (2023)

11530 Background: The treatment of metastatic or unresectable osteosarcoma after standard chemotherapy remains a significant clinical challenge. Connexin 43 (Cx43) hemichannel has been suggested to be a key regulator of bone homeostasis and represents a new target for bone and breast cancer. ALMB-0168, a first-in-class therapeutic antibody agonist for Cx43 hemichannel, has been shown to suppress the growth and migration of osteosarcoma and breast cancer bone metastases in preclinical studies. Methods: Patients ≥16 years with histologically confirmed osteosarcoma who progressed after standard chemotherapy were eligible. This study consists of accelerated titration followed by a 3+3 design with 7 planned ALMB-0168 dose levels (1, 3, 6, 12, 18, 24, and 30 mg/kg) administered intravenously once every 3 weeks and then dose expansion at the potential recommended phase 2 dose (RP2D). Primary endpoints are safety and tolerability. Adverse events are rated according to the NCI CTCAE v5.0. Key secondary endpoints are overall response rate (ORR) and disease control rate (DCR) assessed using RECIST v1.1. Results: As of August 21, 2022, 14 patients (10 males, 4 females) with median age 27.5 years (range 16–38 years) were enrolled; ECOG PS was 0 in 7 patients (50.0%), 1 in 6 patients (42.9%) and 2 in 1 patient (7.1%). 5 patients received ≥2 prior lines of therapy. Six dose levels (1-24 mg/kg) have been completed in this ongoing study with no dose-limiting toxicities reported. Treatment related adverse events (TRAEs) of any grade occurred in 10 (71.4%) patients and were Grade 3 in 1 patient (infectious pneumonia); no events were Grade 4 or 5. Common TRAEs ( &gt; 10%) were proteinuria (21.4%), anemia (21.4%), hematuria (14.3%), and increased aspartate aminotransferase (14.3%). No Cx43-related cardiac events or severe hepatic events were observed. A total of 13 patients were evaluable for response. ORR was 15.4% (2/13, 95% CI: 1.9–45.5%), including 2 partial responses (PR), 1 patient each at 6 mg/kg and 18 mg/kg. The patient at 6 mg/kg, who had ≥3 prior lines of therapy and lung metastases, achieved durable disease control with stable disease (SD) for 33 weeks followed by PR for 8+ weeks (at the time of analysis). The DCR was 53.8% (7/13, 95% CI: 25.1–80.8%) with 2 PRs and 5 SDs. Conclusions: ALMB-0168 demonstrated encouraging efficacy and tolerable safety in patients with metastatic or unresectable osteosarcoma after standard chemotherapy in a phase 1 dose-escalation trial. Dose escalation is ongoing and dose expansion will start at the potential RP2D levels. Clinical trial information: NCT04886765 .
Preclinical evidence for synergistic effects of autophagy inhibitor and alpelisib in PI3KCA mutated non-small cell lung cancer: Implications for future clinical trials.
Authors: Byoung Yong Shim, Sang-Bin Lee, Hyunho Kim, Hyung Soon Park, Ho Jung An
Journal: Journal of Clinical Oncology (2023)

e21022 Background: The PI3K pathway is frequently activated in a variety of cancers including non-small cell lung cancer (NSCLC). PI3K mutation is associated with worse response to chemotherapy and consequently decrease the effectiveness of single administration of anticancer drugs. In this study, we checked the therapeutic efficacy of alpelisib either alone or in combination with an autophagy inhibitor for the treatment of NSCLC. Methods: We treated alpelisib and autophagy inhibitors in human NSCLC cell lines and measured the cell viability and protein expression of autophagy indicators, p62 and LC3B. Co-treatment of alpelisib and autophagy inhibitors significantly decrease the cell viability and proliferation compared to alpelisib alone. Based on the results of the combination experiment of alpelisib and autophagy inhibitors, Chloroquine (CQ) was selected for further study. Co-treatment of alpelisib and CQ significantly increase apoptosis and decrease tumor-related protein expression in in vitro and in vivo. Results: Our data demonstrates that alpelisib and autophagy inhibitor have a synergistic efficacy against NSCLC in vitro and in vivo. Conclusions: Based on these results, a Phase 1 clinical trial is currently being planned.
Active bone marrow-sparing to reduce the incidence of grade 3+ acute hematologic toxicity in patients with locally advanced cervical cancer who receive chemoradiotherapy: A single-center prospective randomized controlled trial.
Authors: ShanBing Wang, JiaPei Liu, Kaijian Lei
Journal: Journal of Clinical Oncology (2023)

5524 Background: Acute haematologic toxicity is the most common side effect of chemoradiotherapy in patients with locally advanced cervical cancer .We aim to test the efficacy of single-photon emission computed tomography-defined active bone marrow-sparing volumetric-modulated arc therapy in reducing grade 3+ acute hematologic toxicity (HT) in locally advanced cervical cancer patients treated with chemoradiotherapy. Methods: This was a prospective, single-center, open label, randomized clinical trial that enrolled locally advanced cervical cancer patients. Participants were randomized to the 99m Tc sulfur colloid SPECT-defined ABMS VMAT (ABMS group) or control group, who received weekly cisplatin concurrently with volumetric-modulated arc therapy followed by high-dose-rate intracavitary brachytherapy. The ABMS group additionally received SPECT-defined ABM dose constraints. The primary endpoint was the incidence of grade 3+ acute hematologic toxicity.Secondary objectives included acute gastrointestinal toxicity, planning Target Volume (PTV) coverage, dosimetric parameters of organs at risk (OARs), progression-free survival (PFS), overall survival (OS). Results: A total of 192 FIGO stage IB-IIIB patients were randomized treated (96 each in the ABMS control groups). The median follow-up was 24.0 months. The incidence of grade 3+ acute hematologic toxicity in the ABMS group was significantly lower than that in the control group (32.3% vs 53.1%, p&lt;0.01). The number of patients completing five cycles of cisplatin was 88.5% in the ABMS group and 75% in the control group, and the difference was significant (p=0.02). There were no significant differences in the mean dose to 95%, 97% and 99%of the PTV between the ABMS group (45.1 Gy, 44.6 Gy, and 43.3 Gy, respectively) and the control group (45.4 Gy, 44.8 Gy, and 43.6 Gy). There were no differences in dosimetric parameters of OARs ,acute gastrointestinal toxicity, 2-year PFS or 2-year OS between the two groups. Patients in the control group had nonsignificantly worse 2-year distant metastasis than patients in the ABMS group (17.8% vs. 11.1%, p=0.19). Conclusions: ABMS VMAT significantly reduced grade 3+ acute HT and improved chemotherapy delivery compared with the control treatment. We found weak evidence of the effect of ABMS VMAT on distant metastasis. Clinical trial information: ChiCTR-IOR-16010214 .
Patterns of ovarian cancer care in an elderly population in Australia: A prospective cohort study from the National Gynaecology Oncology Registry (NGOR).
Authors: Mahendra Naidoo, Clare L. Scott, Orla McNally, Rob Rome, Sharnel Perera, John Raymond Zalcberg
Journal: Journal of Clinical Oncology (2023)

5572 Background: Elderly women with ovarian cancer are often undertreated in comparison to best practice. The National Gynae-Oncology Registry (NGOR) is Australia’s first country-wide clinical quality registry (CQR) measuring compliance with optimal care defined by a set of clinical quality indicators (CQIs). Objectives: To assess compliance with a predefined set of CQIs for elderly women with newly diagnosed ovarian cancer aged &gt; 75 compared to non-elderly women aged &lt;75 years of age from the NGOR sites. Methods: All women with newly diagnosed ovarian cancer from May 2017 – July 2022 were eligible for inclusion. Data were collected from medical records and relevant hospital linked databases by expert data managers. Results: A total of 1590 women were eligible for inclusion from 21 hospitals across 5 Australian states. The CQI data were subsequently aggregated and are summarised in the table. The proportion of elderly women receiving first-line chemotherapy with a platinum and taxane doublet was significantly lower compared to non-elderly (60% vs 89%, p &lt; 0.001). The proportion of women with sub-optimally debulked or Stage IV cancer who received first-line chemotherapy with a platinum/taxane doublet and bevacizumab was significantly lower in elderly women compared to non-elderly (10% vs 30%, p &lt; 0.001) . Enrolment in clinical trials or translational research was significantly lower in elderly women compared to non-elderly (13% vs 21%, p=0.002). The remaining CQIs showed no significant differences between the age groups. Conclusions: In this cohort, most measures of best practice were not significantly different between elderly and non-elderly women, with the exception of elderly women receiving less first line doublet chemotherapy, less doublet chemotherapy with bevacizumab in sub-optimally debulked or Stage IV cancer, and less likely to be enrolled in clinical trials or translational research. While these 3 CQIs represent a minority of the overall list of CQIs, such lack of compliance may result in significant differences in quality of life and overall survival for elderly women with ovarian cancer. Subsequent investigation is therefore warranted to confirm and explain these findings. [Table: see text]
A powerful random forest-based pipeline for accurately identifying the structural variants on panel sequencing data.
Authors: Guiwu Zhuang, Yu-Long Chen, Hongzhen Tang, Wei Wang, Peng Wang, Edmond Gao, Shencun Fang
Journal: Journal of Clinical Oncology (2023)

e18898 Background: Numerous studies have reported that the identification of structural variants (SVs) can provide ideal targets for cancer targeting therapy. However, on the one hand, the current algorithms exhibited different performances in detecting different types and sizes of SVs; on the other hand, the whole-genome/exome sequencing for detecting SVs is costly, and only a portion of SVs can be used to guide the clinical treatment of cancer patients. Therefore, developing a powerful, highly accurate, and cost-effective pipeline to detect SVs for clinical application is urgently required. Methods: Based on simulated sequencing data, four common SV detection tools (Delly, Lumpy, SvABA, and Manta) were used to select the best performance one. This tool will be used for detecting SVs in panel sequencing data. Then, Integrative Genomics Viewer (IGV) was used to annotate these SVs as true positive (TP) and false positive (FP) SVs. These annotated TP and FP SVs were used as input in the random forest classifier (RFC) to train a model for predicting the true or false positive SVs. Two independent testing cohorts and standards were used to validate this constructed pipeline. In addition, IHC/FISH experiments were performed to further validate these predicted TP SVs. Results: In the simulation data, the detection tool with the highest SVs identification sensitivity was Delly. By Delly, a total of 1,303 SVs in 384 tumor samples were detected. Based on annotated TP and FP SVs, an RFC model was constructed in the training cohort, which predicted 334 and 560 TP and FP SVs, respectively. The accuracy rates (AR) were 99.85% and 100% of TP and FP SVs, respectively. The predicted TP and FP SVs by constructed pipeline also showed a high accuracy rate in cohort 1 (98.96% and 99.24% of TP and FP SVs, respectively), cohort 2 (98.48% and 100% of TP and FP SVs, respectively), and standards (the mean accuracy rate was 90%). Finally, based on these TP SVs predicted by the constructed pipeline, FISH/IHC experiment results further verified the robustness of this pipeline (the man accuracy rate was 95.83%). Conclusions: The constructed random forest-based pipeline can robustly and accurately identify SVs based on panel sequencing data, which will be helpful for clinical decision-making.